WO 00/50391, published Aug. 13, 2000, discloses compounds having a sulfonamide moiety that are useful for the treatment and prevention of Alzheimer""s Disease and other diseases relating to the deposition of amyloid protein.
In view of the present interest in the treatment or prevention of neurodegenerative diseases, such as Alzheimer""s disease, a welcome contribution to the art would be compounds for use in such treatment or prevention. This invention provides such a contribution.
This invention provides compounds that are inhibitors (e.g., antagonists) of Gamma Secretase and have the formula: 
or a pharmaceutically acceptable salt or solvate thereof, wherein:
(A) R1 is selected from:
(1) unsubstituted aryl;
(2) aryl substituted with one or more (e.g., 1-3) R5 groups;
(3) heteroaryl; or
(4) heteroaryl substituted with one or more (e.g., 1-3) R5 groups;
(B) R2 is selected from:
(1) alkyl;
(2) xe2x80x94X(CO)Y;
(3) xe2x80x94(CR32)1-4X(CO)Y; or
(4) any of the groups for R1;
(C) Each R3 is independently selected from:
(1) H, or
(2) alkyl;
(D) Each R3A is independently selected from:
(1) H; or
(2) alkyl;
(E) R4 is independently selected from:
(1) halogen;
(2) xe2x80x94CF3;
(3) xe2x80x94OH;
(4) xe2x80x94Oalkyl;
(5) xe2x80x94OCF3;
(6) xe2x80x94CN;
(7) xe2x80x94NH2;
(8) xe2x80x94CO2alkyl;
(9) xe2x80x94CONR6R7;
(10) -alkylene-NR6R7;
(11) xe2x80x94NR6COalkyl;
(12) xe2x80x94NR6COaryl;
(13) xe2x80x94NR6COheteroaryl; or
(14) xe2x80x94NR6CONR6R7;
(F) R5 is independently selected from:
(1) halogen;
(2) xe2x80x94CF3;
(3) xe2x80x94OH;
(4) xe2x80x94Oalkyl;
(5) xe2x80x94OCF3;
(6) xe2x80x94CN;
(7) xe2x80x94NH2;
(8) xe2x80x94CO2alkyl;
(9) xe2x80x94CONR6R7;
(10) alkylene-NR6R7;
(11) xe2x80x94NR6COalkyl;
(12) xe2x80x94NR6COaryl;
(13) xe2x80x94NR6COheteroaryl;
(14) xe2x80x94NR6CONR6R7;
(G) X is selected from:
(1) xe2x80x94Oxe2x80x94;
(2) xe2x80x94NH;
(3) xe2x80x94N-alkyl; or
(H) Y is selected from:
(1) xe2x80x94NR6R7; or
(2) xe2x80x94N(R3)(CH2)2-6NR6R7;
(I) R6 and R7 are independently selected from:
(1) H;
(2) alkyl;
(3) cycloalkyl;
(4) -arylalkyl;
(5) -heteroarylalkyl;
(6) 
(7) 
(J) R6 and R7 taken together with the nitrogen atom to which they are bound form a heterocycloalkyl group selected from: 
(K) Each R8 is independently selected from:
(1) alkyl; or
(2) alkyl substituted with 1 to 4 hydroxy groups;
(L) Each R9 is independently selected from:
(1) H;
(2) alkyl;
(3) alkyl substituted with 1 to 4 hydroxy groups;
(4) cycloalkyl;
(5) cycloalkyl substituted with 1 to 4 hydroxy groups;
(6) -arylalkyl;
(7) -heteroarylalkyl;
(8) xe2x80x94COOalkyl; or
(9) any of the groups for R1;
(M) Each R10 is independently selected from:
(1) H; or
(2) alkyl;
(N) m is 0 to 3, and n is 0 to 3, such that m+n is 1, 2, 3 or 4;
(O) p is 0 to 4;
(P) r is 0 to 4;
(Q) s is 0 to 3; and
(R) with the proviso that compounds of formula 1.0 do not include: 
This invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of formula 1.0 and at least one pharmaceutically acceptable carrier.
This invention also provides a method for inhibiting gamma-secretase comprising administering an effective amount of a compound of formula 1.0 to a patient in need of treatment.
This invention also provides a method of treating neurodegenerative diseases comprising administering an effective amount of a compound of formula 1.0 to a patient in need of treatment.
This invention also provides a method of inhibiting the deposition of amyloid protein (e.g., amyloid xcex2 protein) in, on or around neurological tissue (e.g., the brain) comprising administering an effective amount of a compound of formula 1.0 to a patient in need of treatment.
This invention also provides a method of treating Alzheimer""s disease comprising administering an effective amount of a compound of formula 1.0 to a patient in need of treatment.
As used herein the following terms have the following meanings unless otherwise defined:
Patient includes both humans and other mammals. xe2x80x9cMammalxe2x80x9d means, humans and other animals.
alkoxy: represents a xe2x80x94Oalkyl group wherein alkyl is as defined below;
alkyl: represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms, said alkyl group being optionally substituted with one or more (e.g., 1, 2 or 3) substituents independently selected from: (1) halogen, (2) xe2x80x94OH, (3) xe2x80x94O(alkyl), preferably xe2x80x94O(C1-C6)alkyl, and most preferably xe2x80x94OCH3, (4) xe2x80x94NH2, (5) xe2x80x94NH(alkyl), preferably xe2x80x94NH((C1-C6)alkyl), and most preferably xe2x80x94NHCH3, (6) xe2x80x94N(alkyl)2 wherein each alkyl group is independently selected, preferably xe2x80x94N((C1-C6)alkyl)2 wherein each alkyl group is independently selected, and most preferably xe2x80x94N(CH3)2 or (7) xe2x80x94S(alkyl), preferably xe2x80x94S((C1-C6)alkyl), and most preferably xe2x80x94SCH3;
alkylene: represents a xe2x80x94(CH2)qxe2x80x94 group wherein q is 1 to 20, generally 1 to 6 and more usually 1 to 4, optionally one or more (e.g., 1 to 3, or 1 to 2) hydrogens in said alkylene group can be replaced with the same or different alkyl group (preferably xe2x80x94(C1-C6)alkyl, most preferably xe2x80x94(C1 to C3)alkyl, more preferably xe2x80x94(C1-C2)alkyl) such that the total number of carbons in the entire alkylene group is 2 to 20, also said alkylene group can be optionally substituted with one or more (e.g., 1 to 3) substituents independently selected from the group consisting of: (1) halo; (2) xe2x80x94OH; (3) xe2x80x94O(alkyl), preferably xe2x80x94O((C1-C6)alkyl), and most preferably xe2x80x94OCH3; (4) xe2x80x94NH2; (5) xe2x80x94NH(alkyl), preferably xe2x80x94NH((C1-C6)alkyl), and most preferably xe2x80x94NHCH3; (6) xe2x80x94N(alkyl)2 wherein each alkyl group is independently selected, preferably xe2x80x94N((C1-C6)alkyl)2 wherein each alkyl group is independently selected, and most preferably xe2x80x94N(CH3)2; and
(7) xe2x80x94S(alkyl), preferably xe2x80x94S((C1-C6)alkyl), and most preferably xe2x80x94SCH3;
ar: represents aryl as defined below;
aralkyl (arylalkyl): represents an aryl group, as defined below, bound to an alkyl group, as defined above, wherein said alkyl group is bound to a molecule (e.g., a compound of the claimed invention or an intermediate to a compound of the invention);
aryl: represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., phenyl, naphthyl, phenanthryl, tetrahydronaphthyl or indanyl), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment; said carbocyclic group being optionally substituted with one or more (e.g., 1 to 3) substituents independently selected from: (1) halo, (2) alkyl (preferably xe2x80x94(C1 to C6)alkyl), (3) hydroxy, (4) alkoxy (preferably xe2x80x94(C, to C6)alkoxy), (5) xe2x80x94CN, (6) xe2x80x94CF3, (7) amino (xe2x80x94NH2), (8) alkylamino, (9) dialkylamino (wherein each alkyl group is independently selected), (10) aryl (e.g., phenyl) (provided that if this aryl group is optionally substituted with one or more aryl groups these latter aryl groups are not further substituted with aryl groups), (11) aralkoxy (provided that if the aryl moiety of said aralkoxy (i.e., arylalkoxy) group is optionally substituted with one or more aryl groups these latter aryl groups are not further substituted with aryl groups), (12) aryloxy (e.g., phenoxy) (provided that if the aryl moiety of said aryloxy group is optionally substituted with one or more aryl groups these latter aryl groups are not further substituted with aryl groups), (13) xe2x80x94S(O)0-2-aryl (provided that if the aryl moiety of said xe2x80x94S(O)0-2-aryl group is optionally substituted with one or more aryl groups these latter aryl groups are not further substituted with aryl groups), (14) xe2x80x94COOR11 or (15) xe2x80x94NO2; wherein said R11 represents H, alkyl, aryl (provided that if said aryl moiety is optionally substituted with one or more aryl containing groups these latter aryl containing groups are not further substituted with aryl containing groups), or aralkyl (e.g., benzyl) (provided that if said aryl moiety of said aralkyl group is optionally substituted with one or more aryl containing groups these latter aryl containing groups are not further substituted with aryl containing groups); preferably said optional substituents are independently selected from: halogen, xe2x80x94CF3, xe2x80x94(C1 to C6)alkyl, xe2x80x94(C1 to C6)alkoxy, xe2x80x94OCF3, xe2x80x94NH2, or xe2x80x94CN;
cycloalkyl: represents a cyclic alkyl group of 3 to 10 carbon atoms, and usually 3 to 8 carbon atoms, said cycloalkyl group being optionally substituted with one or more (e.g., 1, 2 or 3) substituents independently selected from:(1) halogen, (2)xe2x80x94OH, (3) xe2x80x94O(alkyl), preferably xe2x80x94O(C1-C6)alkyl, and most preferably xe2x80x94OCH3, (4) xe2x80x94NH2, (5) xe2x80x94NH(alkyl), preferably xe2x80x94NH((C1-C6)alkyl), and most preferably xe2x80x94NHCH3, (6) xe2x80x94N(alkyl)2 wherein each alkyl group is independently selected, preferably xe2x80x94N((C1-C6)alkyl)2 wherein each alkyl group is independently selected, and most preferably xe2x80x94N(CH3)2, (7) xe2x80x94S(alkyl), preferably xe2x80x94S((C1-C6)alkyl), and most preferably xe2x80x94SCH3, or (8) alkyl, preferably xe2x80x94(C1-C6)alkyl;
halogen (halo): represents fluoro, chloro, bromo and iodo;
heteroaryl: represents a monocyclic, bicyclic or tricyclic group having at least one heteroatom (e.g., 1, 2 or 3) independently selected from O, S or N, said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms, e.g., triazolyl, imidazolyl, thienyl, furanyl, quinolyl, isoquinolyl, benzofuranyl, benzopyranyl, benzothienyl, thiazolyl, indolyl, naphthyridinyl, pyridyl (e.g., 2-, 3- or 4-pyridyl) or pyridyl N-oxide (e.g., 2-, 3- or 4-pyridyl N-oxide), wherein pyridyl N-oxide can be represented as: 
and with all available substitutable carbon and heteroatoms of the cyclic group being intended as possible points of attachment, said cyclic group being optionally substituted with one or more (e.g., 1, 2 or 3) groups independently selected from: (1) halo, (2) alkyl (preferably xe2x80x94(C1 to C6)alkyl), (3) aryl, (4) aralkyl, (5) hydroxy, (6) alkoxy (preferably xe2x80x94(C1 to C6)alkoxy), (7) phenoxy, (8) xe2x80x94NO2, (9) xe2x80x94CF3, (10) xe2x80x94OCF3, (11) xe2x80x94CN, (12) amino (xe2x80x94NH2), (13) alkylamino, (14) dialkylamino (wherein each alkyl is independently selected), (15) xe2x80x94COOR11 (wherein R11 is as defined above), or
(16) heteroaryl (provided that if this heteroaryl group, as defined above, is optionally substituted with one or more heteroaryl groups these latter heteroaryl groups are not further substituted with heteroaryl groups); preferably said optional substituents are independently selected from: halogen, xe2x80x94CF3, xe2x80x94(C1 to C6)alkyl, xe2x80x94(C1 to C6)alkoxy, xe2x80x94OCF3, xe2x80x94NH2, or xe2x80x94CN;
heteroaralkyl (heteroarylalkyl): represents a heteroaryl group, as defined above, bound to an alkyl group, as defined above, wherein said alkyl group is bound to a molecule (e.g., a compound of the claimed invention or an intermediate to a compound of the invention);
heterocycloalkyl: represents a cycloalkyl ring as defined above, having one or more (e.g., 1, 2 or 3) heteroatoms independently selected from: O, S, or xe2x80x94NR12xe2x80x94wherein R12 is selected from: H, alkyl, aryl, heteroaryl, ar(C1 to C6)alkyl, or heteroar(C1 to C6)alkyl;
TFA: represents trifluroacetic acid; and
THF: represents tetrahydrofuran.
With reference to the number of moieties (e.g., substituents, groups or rings) in a compound, unless otherwise defined, the phrases xe2x80x9cone or morexe2x80x9d and xe2x80x9cat least onexe2x80x9d mean that there can be as many moieties as chemically permitted, and the determination of the maximum number of such moieties is well within the knowledge of those skilled in the art. For example, xe2x80x9cone or morexe2x80x9d or xe2x80x9cat least onexe2x80x9d can mean 1 to 6 moieties, and generally 1 to 4 moieties, and usually 1 to 3 moieties.
The term xe2x80x9ceffective amountxe2x80x9d as used in the methods and pharmaceutical compositions of this invention means a therapeutically effective amount and is meant to describe an amount of a compound of the present invention to treat a patient having a disease or condition intended to be treated and thus produce a desired therapeutic effect.
Those skilled in the art will appreciate that the term xe2x80x9cneurodegenerative diseasexe2x80x9d has its commonly accepted medical meaning and describes diseases and conditions resulting from abnormal function of neurons, including neuronal death and abnormal release of neurotransmitters or neurotoxic substances. In this instance it also includes all diseases resulting from abnormal levels of beta amyloid protein. Examples of such diseases include, but are not limited to, Alzheimer""s disease, age-related dementia, cerebral or systemic amyloidosis, hereditary cerebral hemorrhage with amyloidosis, and Down""s syndrome.
Lines drawn into the ring systems indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.
Certain compounds of the invention may exist in different isomeric (e.g., enantiomers and diastereoisomers) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.
The compounds of the invention can be administered as racemic mixtures or enantiomerically pure compounds.
Certain compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Preferably:
R1 is aryl substituted with one or more R5 groups, most preferably phenyl substituted with one or more R5 groups, and more preferably phenyl substituted with one or more halo atoms;
n is 0 or 1 and m is 1 or 2 such that m+n is 2 (i.e., (i) n is 0 and m is 2, or (ii) n is 1 and m is 1), most preferably n is 0 and m is 2;
p is 0 or 1, and when p is 1 R4 is halo; and
R2 is xe2x80x94X(CO)Y or xe2x80x94(CR32)1-4X(CO)Y.
Most preferably:
R1 is aryl substituted with one or more R5 groups, more preferably phenyl substituted with one or more R5 groups, and even more preferably phenyl substituted with one or more halo atoms;
n is 0 or 1 and m is 1 or 2 such that m+n is 2 (i.e., (i) n is 0 and m is 2, or (ii) n is 1 and m is 1), most preferably n is 0 and m is 2;
p is 0 or 1, and when p is 1 R4 is halo;
R2 is xe2x80x94X(CO)Y or xe2x80x94(CR32)1-4X(CO)Y;
X is xe2x80x94Oxe2x80x94; and
Y is xe2x80x94NR6R7.
More preferably:
R1 is aryl substituted with one or more R5 groups, even more preferably phenyl substituted with one or more R5 groups, and still even more preferably phenyl substituted with one or more halo atoms;
n is 0 or 1 and m is 1 or 2 such that m+n is 2 (i.e., (i) n is 0 and m is 2, or (ii) n is 1 and m is 1), most preferably n is 0 and m is 2;
p is 0 or 1, and when p is 1 R4 is halo;
R2 is xe2x80x94X(CO)Y or xe2x80x94(CR32)1-4X(CO)Y;
X is xe2x80x94Oxe2x80x94;
Y is xe2x80x94NR6R7; and
R6 and R7 are independently selected from: H, methyl, ethyl xe2x80x94(C3-C8)cycloalkyl, -aryl(C1-C6)alkyl, 4-pyridylmethyl, 
R6 and R7 taken together with the nitrogen atom to which they are bound form a heterocycloalkyl group selected from: 
Representative compounds of the invention include but are not limited to the compounds of Examples 1 to 100. Preferred compounds of the invention are the compounds of Examples 35, 39, 41, 43, 56, 58, 59, 61, 70, 70A, 77, 78, 98, 99 and 100.
Compounds of formula 1.0 can be prepared by various methods well known to those skilled in the art. For example, compounds of formula 1.0, wherein R2 is xe2x80x94X(CO)Y or xe2x80x94(CH2)1-4X(CO)Y (hereinafter represented as xe2x80x94(CH2)0-4X(CO)Y), and X and Y are as previously defined above, can be prepared as shown in Scheme 1. 
Precursor amines or alcohols 2.0 are protected with a suitable protecting group xe2x80x9cPrtxe2x80x9d
to give protected derivative 3.0. Protecting groups for alcohols and amines are well known to those skilled in the art, and include trialkylsilyl groups, alkyl and arylcarbamates, amides, and esters. The protected derivative 3.0 is then treated with a sulfonyl halide R1SO2Hal (where Hal=a halogen) in the presence of a suitable base such as triethylamine or sodium hydride, to give sulfonamide 4.0. The protecting group is removed under appropriate conditions known to those skilled in the art, such as methanolic or aqueous base (e.g., sodium hydroxide or potassium carbonate), aqueous or methanolic acid (e.g., hydrochloric acid) or tetra-n-butylammonium fluoride. This is then converted to various esters, amides, carbamates, and carbonates using methods well known to those skilled in the art. These methods
include reaction with an appropriate carboxylic acid chloride, reaction with a carboxylic acid in the presence of an activating agent such as dicyclohexylcarbodiimide or hydroxybenzotriazole, reaction with an alkyl or arylchloroformate, reaction with an arylchloroformate followed by reaction with an amine or alcohol. Compounds of 2.0 are either commercially available or can be prepared by methods well known in the art as are described in the examples below.
Compounds of formula 1.0 wherein R2 is aryl substituted with one or more R5 groups can be, for example, prepared as described in Scheme 2. 
R13 represents alkyl, aryl or xe2x80x94NR6R7. Aldehyde 5.0 is converted to a variety of substituted compounds via methods well known to those skilled in the art. For example, 5.0 can be treated with a primary or secondary amine in the presence of a reducing agent such as triacetoxyborohydride and in a suitable solvent such as dichloroethane to give an aminoalkyl derivative 1.2. Aldehyde 5.0 can be oxidized to the corresponding carboxylic acid with, for instance, Jones reagent, and then converted to amides (1.3). Alternatively, the acid can be converted to an amine with diphenylphosphorylazide and the amine converted to amides or ureas (1.4). Aldehyde 5.0 can be prepared by methods known in the art and by the methods described in the examples below.
Compounds of this invention are exemplified by the following examples, which should not be construed as limiting the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art.
In the following examples, xe2x80x9cHRMS(MH+)xe2x80x9d refers to the measured high resolution mass of the compound. xe2x80x9cLCMS(MH+); Rt (min)xe2x80x9d refers to the mass and retention time as determined by LC-Mass spectrum carried out on an Alltech Platinum C8 column (33 mmxc3x977 mm ID, 3 micron particle size). Elution conditions for LC/MS are as follows: Solvents: A. Water w/0.05% TFA (v/v); B. Acetonitrile w/0.05% TFA (v/v); Flow Rate: 311 mL/min